Study: New Automated Strategy May Improve Peptide Therapy in PAH

Scientists find more stable way to make peptide drugs for range of diseases

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Researchers have created an automated way to engineer a more stable peptide-based therapy, which could inform the production of new and improved treatments for diseases like pulmonary arterial hypertension (PAH).

The research was led by Yousef Al-Abed, PhD, co-director of the Institute of Bioelectronic Medicine at the Feinstein Institutes for Medical Research, and detailed in a recent study, titled “Thiocarbazate building blocks enable the construction of azapeptides for rapid development of therapeutic candidates,” published in the journal Nature Communications.

“Peptide drugs are a crucial resource for patients and the global pharmaceutical industry,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes and the Karches family distinguished chair in medical research, in a press release. “Dr. Al-Abed and his team invented a fully automated chemical strategy using novel chemistry to make new peptide drugs which is an important new avenue for peptide drug discovery.”

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Developing a more stable peptide therapy

Peptides are short sections of amino acids, the building blocks of proteins. They have garnered recent interest as therapeutic molecules for many diseases, including for pulmonary hypertension.

By selecting out the specific section of a protein that has a therapeutic effect, these peptides are thought to be increasingly specific to their biological target — and likely to elicit fewer side effects.

A major drawback, however, is that enzymes in the body tend to rapidly degrade these peptides, limiting their therapeutic capacity. This presents a hurdle in moving peptide therapy beyond the laboratory and into the clinic.

“Peptides as drug candidates are easy to discover yet difficult to develop as final drugs because of their fast degradation in our body,” said Al-Abed. “A technology that circumvents these problems inherent to native peptides will change the future landscape of drug discovery.”

A potential solution to this problem are azapeptides, which essentially are peptides that have been edited, or modified in the lab, to be less vulnerable to degradation. Still, generating these azapeptides has historically been considered a challenge, the researchers noted.

Now, Al-Abed and his team have developed an easy-to-use peptide-editing technique in which specific amino acids in the peptide — those that are vulnerable to the body’s degradative enzymes — are replaced with a more stable version.

The replacement doesn’t change the therapeutic properties of the peptide.

To test their new technology, the researchers chose to edit well-characterized peptides with a fast degradation. One of the peptides they chose is called FSSE (P5779), which works to inhibit high mobility group-box 1 (HMGB1), a pro-inflammatory molecule.

FSSE has been shown to be therapeutic in preclinical models of PAH. Treatment with the peptide improved heart function and lessened vascular remodeling — structural changes in the blood vessels that have been implicated in PAH — as well as prolonged survival in a rat PAH model.

A certain azapeptide derivative of FSSE that the researchers developed had increased stability in mouse blood compared with standard FSSE, but with a comparable ability to inhibit HMGB1.

It also could lower levels of tumor necrosis factor-alpha, an inflammatory protein released by certain immune cells in response to HMGB1.

Further experiments in mice suggested the azapeptide had therapeutic effects in diabetes and liver toxicity.

Ultimately, according to researchers, the platform can be used to edit therapeutic peptides for a range of conditions in addition to PAH, including metabolic disease, influenza, Crohn’s disease, arthritis, and irritable bowel syndrome.

“We envision this platform azapeptide synthesis technology could accelerate the advancement of both existing and unique peptide-based agents as therapeutics,” the researchers wrote.

Added Al-Abed: “Our technology provides a platform of tools that enable minimal modification of any peptide at highly prone degradation sites, thereby increasing its life span in our body, allowing it more time to find its target and neutralize it.”

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